The present invention relates to a method for producing a polyalkylene glycol derivative having a terminal amino group, a polymerization initiator for use in the same, and an alcohol compound as a raw material of the polymerization initiator.
Recently, in the drug delivery system, a method for encapsulating drugs in a polymer micelle using a block copolymer formed from a hydrophilic segment and a hydrophobic segment has been proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267). By using the method, the polymer micelle functions as a carrier for drugs, producing various effects including sustained release of drugs in vivo and concentrated dosage at an affected region.
As the hydrophilic segment, many examples with use of a polyalkylene glycol skeleton are proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267). A compound having a polyalkylene glycol skeleton has low toxicity in vivo, and enables excretion by the kidney to be delayed. Consequently, in comparison with a compound having no polyalkylene glycol skeleton, the retention time in blood can be prolonged. As a result, with use of a drug micellized with a polyalkylene glycol derivative, the dosage amount or dosage frequency can be reduced.
Among polyalkylene glycol derivatives, a compound having an amino group at an end can lead to a block copolymer composed of a polyalkylene glycol skeleton and an amino acid skeleton through a ring-opening polymerization reaction with α-amino acid-N-carboxy anhydride. Many examples with use of the produced block copolymer for encapsulating drugs in a polymer micelle are proposed (refer to, for example, Japanese Patent No. 2690276, Japanese Patent No. 2777530, and Japanese Patent Application Laid-Open No. 11-335267).
Synthesis methods of such polyalkylene glycol derivatives having an amino group at an end are also known (refer to, for example, Japanese Patent No. 3050228 and Japanese Patent No. 3562000). In these methods, after polymerization of an alkylene oxide with use of a metal salt of monohydric alcohol as a polymerization initiator, a polymer end is converted to a hydroxyl group, and then to a 2-cyanoethoxy group, finally leading to an amino group-containing substituent group (3-amino-1-propoxy group) through hydrogen reduction of the cyano group.
Other methods for synthesizing a polyalkylene glycol derivative having an amino group include, for example, a method in which ethylene oxide is polymerized with a polymerization initiator the amino group of which is silyl-protected, and then deprotection is performed to lead an amino group (refer to Bioconj. Chem. 1992, 3, 275-276, and Japanese Patent No. 4581248). However, in this method, there is a problem that the end is limited to a 2-amino-1-ethoxy group. Moreover, it is considered that the reactivity is low and the problem is that a long time, as long as 96 hours, are required for increasing the molecular weight up to 6000 (refer to Bioconj. Chem. 1992, 3, 275-276).